A new study compared the efficacy and safety of sitagliptin with dapagliflozin in patients with both type 2 diabetes and mild renal impairment. Sitagliptin showed greater glycemic efficacy over dapagliflozin when added onto existing therapy.

Included in the 24-week study were 613 patients with HbA1c 7.0-9.5% and eGFR 60-<90 ml/min/1.73m2 taking metformin ± sulfonylurea. Eligible participants were randomized into one of two groups, the first of which included patients taking sitagliptin 100 mg once daily and the other group taking dapagliflozin 5 mg titrated up to 10 mg once daily (n=307 and n=306, respectively).

A longitudinal data analysis model was used to test whether sitagliptin showed non-inferiority to dapagliflozin in reducing HbA1c at 24 weeks. Primary endpoints included fasting plasma blood glucose, 2-hour post-prandial blood glucose, post-prandial insulin and glucagon, insulin-to-glucagon ratio, and the change in baseline in HbA1c at 24 weeks. Baseline mean HbA1c was 7.7% and 7.8%, and mean eGFR was 79.4 ml/min/1.73m2 and 76.9 ml/min/1.73m2 for the sitagliptin and dapagliflozin groups, respectively.

At 24 weeks, the sitagliptin group showed a greater mean change in HbA1c from baseline vs. the dapagliflozin group (between-group difference, -0.15% [95% CI, -0.26 to -0.04] p=0.006). These results confirmed both the non-inferiority and superiority of sitagliptin over dapagliflozin in mean reduction of HbA1c, meeting the prespecified criteria.

Investigators also observed a greater percentage of patients reaching goal HbA1c of <7% in the sitagliptin group, with 43% of patients reaching HbA1c goal in the sitagliptin group vs. only 27% reaching HbA1c goal in the dapagliflozin group (between-group difference, 15.5 [95% CI, 7.7-23.2]). No significant between-group difference was noted for the 2-hour post-prandial glucose excursion.

In addition to greater control of glycemic, the sitagliptin group also displayed a lower number of adverse events, with only 48.9% of participants experiencing one or more adverse events compared with 51.6% in the dapagliflozin group.

Overall, investigators gave compelling evidence for the addition of sitagliptin therapy in patients with type 2 diabetes and mild renal insufficiency whose glucose levels were inadequately controlled on metformin ± sulfonylurea. Compared with dapagliflozin, sitagliptin proved to be more advantageous in regards to not only glycemic efficacy, but also safety and tolerability. As the number of patients with type 2 diabetes and comorbid conditions continues to rise, further studies are needed to better serve clinicians when evaluating therapy for their patients.

Practice Pearls:

In patients with type 2 diabetes and mild renal insufficiency who are inadequately controlled on metformin with or without sulfonylurea therapy, sitagliptin may be added to reach glycemic goals.

Compared to dapagliflozin, sitagliptin displays a better safety profile in addition to a greater reduction in HbA1c.

Prolonged use of medication increases risk of bowel condition, but exact cause yet to be determined.

Dipeptidyl peptidase-4 inhibitors (DPP-4s) are a class of medication used for treatment of type 2 diabetes. This class of medication is used as a second- or third-line treatment and has many favorable effects, including having lower risk of causing hypoglycemia and not having any effect on body weight. However, inhibition of DPP-4 enzyme can lead to undesirable side effects such as the development of autoimmune conditions — inflammatory bowel disease and others. Data shows that patients with inflammatory bowel disease have lower serum DPP-4 enzyme levels. The goal of this study was to determine whether prolonged use of DPP-4 inhibitors can have increased incidence of inflammatory bowel disease in patients with type 2 diabetes.

Inclusion criteria for this study was that participants had to be at least 18 years of age and newly started on non-insulin antidiabetic drugs such as metformin, sulfonylureas, meglitinides, thiazolidinediones, acarbose, DPP-4 inhibitors, glucagon-like peptide 1 receptor agonists, or sodium-glucose co-transporter 2 inhibitors. Patients with any insulin therapy, or female patients with a history of polycystic ovary syndrome or a history of gestational diabetes were excluded from this study. Any patients with previous history of having inflammatory bowel disease were also excluded. Patients were followed until diagnosis of inflammatory bowel disease, ischemic colitis, or death from any cause, or the end of the study period (June 30, 2017), whichever occurred first. Overall, a total of 141,170 patients were included in the analysis of the results.

Results of this study showed that a total of 208 incidents of inflammatory bowel disease occurred (about 37.7 per 100,000 person years). About 21.6% participants had received at least one prescription of a DPP-4 inhibitor during the study period. Baseline characteristics of the enrolled population showed that users of DPP-4 inhibitors were older, more likely to have microvascular complications, more likely to have used non-steroidal anti-inflammatory medications, and more likely to have a higher hemoglobin A1C concentration. According to the results, use of DPP-4 inhibitors was 75% more likely to increase risk of inflammatory bowel disease. It was also found that use of DPP-4 inhibitors was associated with more than a twofold increase in the risk of ulcerative colitis and no risk for Crohn’s disease. The development of inflammatory bowel disease was highest between two to four years after the start of DPP-4 inhibitors.

The exact mechanism of how DPP-4 inhibitors cause inflammatory bowel disease is yet to be understood. It is known that they modulate gastric hormones, which are elevated in patients with inflammatory bowel disease. The expression of DPP-4 enzyme was elevated on T-cells in patients with inflammatory bowel disease but overall serum concentration of this enzyme was lower compared to healthy individuals.

In conclusion, additional studies need to be performed to prove the accuracy of results from this study. Also, studies need to performed to understand the exact mechanism of how DPP-4 inhibitors increase the risk of inflammatory bowel disease and what actions, if any, can be taken to reduce this risk. Physicians should be aware of the risks of DPP-4 inhibitors and try to avoid its use in patients who might be at a higher risk, such as those with a family history of autoimmune conditions. Patients with persistent gastrointestinal symptoms, such as diarrhea, abdominal pain, flatulence, etc., should be closely monitored for worsening of symptoms.

One of the strengths of this study was that it excluded prevalent users and this eliminated possible biases. Results of this study also stayed very consistent across a variety of sensitivity analysis showing that very little bias was involved. One of the limitations of this study was that prescriptions were written by general practitioners and not specialists. Although minimal, this can lead to some misclassification.

Practice Pearls:

Prolonged use of DPP-4 inhibitors are associated with an overall 75% increase in the risk of inflammatory bowel disease, more than a twofold increase in the risk of ulcerative colitis and no risk for Crohn’s disease in patients with type 2 diabetes.

Use of DPP-4 inhibitors should be avoided in patients who are at high risk of developing autoimmune diseases.

The exact mechanism of how DPP-4 inhibitors cause inflammatory bowel disease is unknown and needs to be further studied.

]]>Understanding The Gap Between Efficacy In Randomized Trials And Effectiveness In Real-World Use Of GLP-1RA and DPP-4 Therapieshttp://www.diabetesincontrol.com/understanding-the-gap-between-efficacy-in-randomized-trials-and-effectiveness-in-real-world-use-of-glp-1ra-and-dpp-4-therapies/
Sat, 13 Jan 2018 00:06:00 +0000http://www.diabetesincontrol.com/?p=57017

Patients are not seeing the expected results because of medication adherence.

Patients are not seeing the expected results because of medication adherence.

As the rate of obesity, type 2 diabetes, and cardiovascular disease steadily increases, so does the demand for accessible and effective treatment options. Over the last 10 years, approximately 40 new medications for the treatment of type 2 diabetes have been developed. Despite these advances, less than 50% of patients with type 2 diabetes in the United States have achieved an HbA1c < 7%. Randomized controlled trials often yield promising results with many patients experiencing significant reductions in HbA1c, fasting plasma glucose, and improved cardiovascular outcomes. However, when practitioners implement these new drugs into their practice, they are often met with significantly lower patient improvements. Some postulate that patients who agree to enroll in a clinical trial are more likely to be concerned about their health and are therefore more adherent to the medication regimen, which leads to better trial outcomes. Others propose that patients in trials are more likely to be on maximum dosing and in real-world scenarios practitioners may prescribe lower dosages. Recent studies have shown that adherence rates vary from 20-50% depending on the method of assessment and class of medication. Poor adherence is directly correlated to increased healthcare costs, reduced glycemic control, and ultimately poorer patient outcomes. Therefore, researchers aimed to compare the change in HbA1c between patients in a real-world setting and patients in a randomized control trial after the initiation of GLP-1 agonist or DPP-4 therapy.

An estimated multivariate model, combined with descriptive real-world and trial patient information was used to describe the differences between the two groups. Patient accounts of adherence are often inaccurate and to avoid potential bias, the critical measure used was based on the percentage of days covered (PDC). The PDC is currently endorsed by the National Quality Forum and the Medicare Star Ratings and is commonly used in quality measures and adherence literature. To evaluate the change in HbA1c, researchers accessed the Optum/Humedica Smartfile database. This database is one of the largest and most comprehensive databases that includes administrative claims and electronic records. The index date for real-world patients was the date of the first fill of a DPP-4 or GLP-1 agonist prescription with baseline measurements being 1 year prior to that fill. The follow-up period was the 1-year timeframe between baseline and subsequent HbA1c measurement. The GLP-1 agonists and DPP-4 medications selected were based on the number of real-world patients that were taking that drug. Because <5% of real-world patients were taking linagliptin and alogliptin, both of those drugs were excluded from the study. Publications of randomized controlled trials involving liraglutide, exenatide, sitagliptin and saxagliptin instead were selected. The primary outcome was changed in HbA1c measured from baseline (up to 90 days before initiation of therapy or 14 days after initiation of therapy) to a second HbA1c measurement (365 +/- 90 days after initiation of treatment). Adherence was estimated using the PDC with a non-overlapping supply of the medication. Adherence was classified as a PDC > 80%. Any changes in the patient’s medication regimen (i.e. discontinuance, change in regimen) was documented with discontinuance being defined as absence of the drug for 30 days with no subsequent fills through the end of the trial.

A total of 873 real-world patients met the inclusion criteria with 652 patients receiving DPP-4 therapy and 221 patients receiving GLP-1 agonist therapy. A total of 11 randomized controlled trials were selected and were comprised of 7 GLP-1 agonist trials and 4 DPP-4 trials. Baseline HbA1c levels were similar for real-world and trial patients taking a GLP-1 agonist, but the mean baseline HbA1c was lower for trial patients receiving DPP-4 therapy. During the follow-up period, approximately 29% of patients taking GLP-1 agonists and 37% taking DPP-4s were adherent to their medication regimen. Roughly 40% of real-world patients discontinued either a GLP-1 agonist or DPP-4 and less than half of that group was restarted on another medication. The overall reduction in HbA1c levels for real-world patients was similar between the two groups [GLP-1A: -0.52%, DPP-4: -0.51%]. This was in stark contrast to the trial patients [GLP-1A: -1.30%, DPP-4: -0.68%].

Adherent real-world patients taking GLP-1 agonists demonstrated more than double the decrease in HbA1c. The gap between real world and trial patients [GLP-1A: 0.51%, DPP-4: 0.18%] can be explained by differences in adherence, addition of other medications, and baseline characteristics. However, medication adherence accounted for approximately 75% of the estimated HbA1c gap between real-world and trial patients. We are not seeing real-world benefits in patients taking GLP-1 agonists or DPP-4s, and medication adherence is a primary reason. The results of this study stress the urgent need to reinforce medication adherence and evaluate how practitioners are educating patients on the importance of taking their medications.

Practice Pearls:

Medication adherence is 75% responsible for the difference between trial and real-world patient HbA1c improvement.

Less than half of patients discontinued on a GLP-1 agonist or DPP-4 were restarted on another regimen

Reference:

Carls, Ginger S., et al. “Understanding the Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use of GLP-1RA and DPP4 Therapies in Patients With Type 2 Diabetes.” Diabetes Care(2017): dc162725.

Jessica Lambert, University of South Florida College of Pharmacy, Doctor of Pharmacy Candidate 2018

Additive glucose-lowering effect of a dipeptidyl peptidase-4 (DPP4) inhibitor and an alpha-glucosidase inhibitors (AGI) might be beneficial in patients with T2DM.

According to a literature review published online on September 26, 2017 in the Journal of Diabetes Investigation by researchers from Republic of Korea, the addition of a dipeptidyl peptidase-4 (DPP4) inhibitor to diabetic treatment in patients with T2DM who are inadequately controlled with an alpha-glucosidase inhibitors (AGI) may provide an additive or synergistic glucose-lowering effect as the drugs have a complementary mechanism of action, without further increasing the risk of weight gain and hypoglycemia. The dipeptidyl peptidase-4 (DPP4) inhibitor increases plasma concentration of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which leads to an increase in insulin secretion and decreases glucagon secretion. The alpha-glucosidase inhibitors (AGI) such as acarbose, miglitol, and voglibose inhibit the hydrolysis of carbohydrate, which delay its absorption from the small intestine.

Researchers conducted a systematic review and meta-analysis search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov through October 2016. Any randomized controlled trials written in English that compared DPP4i plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with T2DM were eligible for inclusion. Studies that are duplicates or extensions of another study were excluded. Researchers retrieved 756 relevant studies of which data from 5 studies with a total of 1,799 study participants (845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI) were included for the meta-analysis. A mean study duration is 14 weeks.

The result from all 5 studies reported the changes in HbA1c level and fasting plasma glucose level from baseline. DPP4i/AGI correlated with a greater reduction in HbA1c level than PCB/AGI (Weight Mean Difference -1.2%; 95% CI -1.6% to -0.8%) and a greater reduction in fasting plasma glucose levels than PCB/AGI (Weight Mean Difference -26.8 mg/dL; 95% CI -39.9 to -13.8 mg/dL). Four out of 5 studies reported reduction in two-hour postprandial plasma glucose levels was greater in the DPP4i/AGI group than in the PCB/AGI group (Weight Mean Difference -34.5 mg/dL; 95% CI -52.9 to -16.1mg/dL).

Weight gain and hypoglycemia are two unwanted side effects when increasing the dose or adding another antidiabetic drug in patients with consistently high blood glucose levels. Four out of five studies reported that the DPP4i/AGI group did not show any significant changes in body weight and risk of hypoglycemia compared with the PCB/AGI group; (Weight Mean Difference 0.1 kg; 95% CI -0.3 to -0.4 kg) and (RR 1.4, 95% CI 0.4 to 4.6), respectively. Some AGIs can reduce appetite and APP4 inhibitors have neutral effects on body weight. Given that the combination of the two agents might be a favorable option for patients with type 2 who are overweight or have obesity. In addition, AGI monotherapy does not cause hypoglycemia, unless it is used in combination with sulfonylureas or insulin. DPP4 inhibitors monotherapy or in combination with insulin are unlikely to cause hypoglycemia. Therefore, the addition of DPP4 inhibitors to AGI therapy does not increase the risk of hypoglycemia.

One of the limitations of the study is that it includes a small number of the included studies. Another limitation is that researchers were unable to compare the outcomes among DPP4 inhibitor plus AGI, placebo plus AGI, placebo plus DPP4 inhibitor, and placebo alone in patients with T2DM who were naïve to DPP4 inhibitors or AGIs. Lastly, most of study participants were Asians whose glucose-lowering responses to incretin-based therapy are known to be greater than in other ethnic groups.

Practice Pearls:

The addition of a DPP4 inhibitor with an AGI therapy in patients with type 2 who have consistently high blood glucose levels achieved a clinically significant improvement in glycemic control.

The addition of a DPP4 inhibitor to an AGI therapy does not increase the risk of weight gain and hypoglycemia.

The combination of a DPP4 inhibitor and an AGI agent is a viable option for patients with T2DM who are overweight or have obesity.

Sitagliptin (Januvia) is a DPP-4 antidiabetic oral agent for treating type 2 diabetes. A new warning label regarding the risk of developing heart failure in patients with cardiovascular disease was issued to this drug by the FDA in September 2017. Other drugs within the same class, Nesina and Tradjenta, were also issued this warning, suggesting the associated risk to be a “class-effect” of the DPP-4 inhibitors. To date, no direct studies have linked this drug with increasing risk of cardiovascular events, including heart failure.

Saxagliptin (Onglyza), another DPP-4 inhibitor, was found to increase the risk of hospitalization for heart failure and the risk of hypoglycemic events. This study found that more patients in the Saxagliptin group than in the placebo group were hospitalized for heart failure.(1) This study happened to be the evidence and reason behind the FDA’s decision to correct Sitagliptin’s package insert. It appears that the FDA issued such warning in a conservative way without a solid controlled trial supporting the cardiovascular risk.

From 2008 until 2015, a major randomized, double-blind, placebo-controlled, event-driven trial was conducted by Duke Clinical Research Institute (DCRI) and the University of Oxford Diabetes Trials Unit (DTU). It evaluated a total of 14,735 patients with established cardiovascular disease. They compared the sitagliptin group vs placebo. The primary endpoint was the risk of developing major cardiovascular events such as nonfatal MI, nonfatal stroke, cardiovascular death, or unstable angina. Mean follow-up was 3 years and included patients from 38 different countries. Baseline characteristics were well balanced for both groups and all cardiovascular and noncardiovascular adverse events were recorded.

There was no significant difference in the primary composite cardiovascular outcome (hazard ratio 0.98 P<0.01). There was also no significant difference in the rate of hospitalization for heart failure, which was reported in 228 patients in the sitagliptin group (3.1%) and 229 in the placebo group (3.1%). The composite outcome of hospitalization for HF or cardiovascular death occurred in 538 patients in the sitagliptin group (7.3%) and 525 in the placebo group (7.2%) (hazard ratio in the ITT analysis, 1.02, P=0.74).

No significant increment in the rate of severe hypoglycemia was seen among patients in the sitagliptin group, as compared with the placebo group. Acute pancreatic events were found to be uncommon and not statistically significant between both groups. There was also no significant difference between the sitagliptin group and the placebo group regarding the overall incidence of infections, cancer, or reported renal failures. Death from any cause occurred in 547 patients in the sitagliptin group (7.5%) and 537 in the placebo group (7.3%) (hazard ratio in the ITT analysis, 1.01, P=0.88).

This study suggested that sitagliptin may be used in diabetes patients with elevated risk of cardiovascular events. In a statistical perspective, this study had enough power to dismiss any association between sitagliptin use and cardiovascular events. On the other hand, these results cannot predict the risk of using sitagliptin when used for longer periods of time or in patients with more complicated diseases. Furthermore, this trial did not include patients with severe renal disease or patients with A1C levels above 8.0%, thus the risk was not determined for these populations. The publication of this article was 2 years prior to the FDA’s decision to issue the warning label to Sitagliptin, which was based on a trial that only included Saxagliptin; however, it is best evidence study of safety and direct cardiovascular effects related to Sitagliptin. Future trials should focus on comparing the risk of HF hospitalization between Sitagliptin, Saxagliptin, other DPP-4 Inhibitors versus placebo.

Practical Pearls:

The use of sitagliptin is not associated with increasing risk of heart failure hospitalization among patients with cardiovascular disease.

The use of sitagliptin is a reasonable treatment for patients with moderate diabetes without severe renal impairment.

All DPP-4 inhibitors have new warning for increasing risk of heart failure hospitalizations in high-risk populations.